Safety and effectiveness of ustekinumab in elderly Crohn's disease patients.

OBJECTIVE: Anti-tumour necrosis factor (TNF) agents are associated with increased infection risk among elderly IBD patients, but little is known about non anti-TNF biologics in this cohort. We examined the safety and effectiveness of ustekinumab in elderly Crohn's patients. METHODS: This retrospective multi-centre cohort study included Crohn's patients ≥60-years old who commenced ustekinumab. We recorded Harvey-Bradshaw index (HBI), concomitant steroid therapy, treatment persistence and new infections or malignancies. Primary outcome was serious infections requiring hospitalisation. RESULTS: Seventy patients were included, with median age of 68 years. 43 (61.4%) had prior anti-TNF exposure, and 15 (21.4%) vedolizumab. Median treatment duration was 12 months, totalling 84 patient-years. Nine serious infections were reported, incidence 106.7/1000 patient-years. Systemic steroids were associated with increased risk of serious infections [odds ratio (OR) 7.83, 95% confidence interval (CI): 1.44-44.32, P = 0.02]. There were 27 "non-serious" infections; 321.4/1000 patient-years. Charlson co-morbidity index (OR 1.49, 95% CI: 1.05-2.12, P = 0.03) and steroid exposure (OR 44.10, 95% CI: 1.75-1112.10, P = 0.02) increased non-serious infection risk (P < 0.05). Mean HBI improved from 8.13 to 4.64 at 6 months and 4.10 at last follow up (P < 0.0001). 12-month treatment persistence was 55.7% (N = 39); 34 (48.6%) were steroid-free. CONCLUSION: Ustekinumab was safe and effective in a cohort of elderly Crohn's disease patients. Infections were mostly mild, not resulting in therapy discontinuation. Serious infection risk was comparable to previously reported rates with anti-TNF agents. Steroid exposure was associated with an increased serious infection risk.

A propensity score-matched, real-world comparison of ustekinumab vs vedolizumab as a second-line treatment for Crohn's disease. The Cross Pennine study II.

BACKGROUND: The optimal choice of biological agents after failure of anti-tumour-necrosis-factor-(TNF)α agent in Crohn's disease (CD) is yet to be defined. AIMS: To assess the effectiveness and safety of ustekinumab compared to vedolizumab as second-line treatment in CD patients who failed anti-TNFα therapy. METHODS: Retrospective analysis of clinical response and remission at 14 and 52 weeks to ustekinumab by physician global assessment (PGA). A propensity score-matched analysis with a cohort treated with vedolizumab was performed. RESULTS: Of 282 patients (mean age 40 ± 15, F:M ratio 1.7:1) treated with ustekinumab, clinical response or remission was reached by 200/282 patients (70.9%) at 14 weeks, and 162/259 patients (62.5%) at 52 weeks. Overall, 74 adverse events occurred, of which 26 were labelled as serious (8.3 per 100 person-year). After exclusion of patients without prior anti-TNFα exposure and patients previously exposed to vedolizumab or ustekinumab, we analysed 275/282 patients (97.5%) on ustekinumab and 118/135 patients (87.4%) on vedolizumab. Propensity score analysis revealed that at 14 weeks, patients treated with ustekinumab were 38% (95% CI 25%-50%; P < 0.001) more likely to achieve clinical remission, while at 52 weeks, the difference of 9% (95% CI -15% to 33%; P = 0.462) was not significant. CONCLUSIONS: Ustekinumab was effective and well tolerated in this real-world cohort. While ustekinumab proved more effective at 14-weeks, we found no statistically significant differences at 52 weeks compared to vedolizumab.

Comparative effectiveness of ustekinumab or vedolizumab after one year in 130 patients with anti-TNF-refractory Crohn's disease.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting. AIM: To compare the effectiveness of ustekinumab and vedolizumab in anti-TNF-refractory Crohn's disease over 12 months. METHODS: Patients commencing ustekinumab or vedolizumab for anti-TNF-refractory Crohn's disease with minimum follow-up of 12 months were included. The primary outcome measure was the difference in steroid-free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid-free remission and clinical response and remission. RESULTS: We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid-free and clinical remission were significantly higher among ustekinumab-treated patients. After adjusting for confounders, steroid-free remission was higher among ustekinumab-treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06-7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89-4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007). CONCLUSIONS: Ustekinumab appeared more effective in treating anti-TNF-refractory Crohn's disease and more patients persisted with therapy.

Microscopic colitis: diagnosis and management.

Microscopic colitis (MC) is a common cause of chronic, non-bloody, watery diarrhoea in older patients. The diagnosis depends on characteristic histological findings. Bile acid malabsorption and autoimmune conditions, including coeliac disease, are more frequently found in patients with MC, but colorectal neoplasia and mortality are not increased. Non-steroidal anti-inflammatory drugs, proton-pump inhibitors, selective serotonin reuptake inhibitors and smoking tobacco confer an increased risk of developing MC. Although a so-called benign disease, which rarely causes serious complications, it does have an impact on the quality of life. Several treatment options exist, but budesonide is the only treatment proven in randomised-controlled trials to be effective and safe for induction and maintenance of remission. This article provides a practical overview for the gastroenterologist looking after patients with MC.

Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration.

Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.

Neuropathic pruritus (itch) in neuromyelitis optica.

BACKGROUND: Neuropathic pruritus (itch) is an uncommon, but well described, symptom in neurology. There are itch-specific neurons in the dorsal horn of the spinal cord. We noted excessive pruritus in patients with neuromyelitis optica (NMO). OBJECTIVE: We aimed to explore the characteristics of pruritus in NMO patients. METHODS: We reviewed case records of a well-defined cohort of 45 serial aquaporin-4 antibody-positive patients visiting the national NMO service. All patients were interviewed. RESULTS: Of the 45 antibody-positive NMO patients, 44 had myelitis and 12 of those 44 (27.3%) patients reported pruritus within a week of other symptoms of transverse myelitis with central cord involvement. In three patients, pruritus was the first symptom of a relapse, while in one case, pruritus was the very first symptom of the index episode of NMO. CONCLUSION: Neuropathic pruritus seems to be a common, but under-recognised symptom of myelitis associated with NMO.